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Arsenic methylation phenotype affects accumulation and retention of arsenic in mice
Citation:
HUGHES, M. F., B. C. EDWARDS, K. HERBIN-DAVIS, AND D. J. THOMAS. Arsenic methylation phenotype affects accumulation and retention of arsenic in mice. Presented at Society of Toxicology 49th annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
As3mt knockout mice displayed a marked retention and altered metabolism of arsenate after repeated daily dosing to steady-state in contrast to wild type mice. Altered retention of arsenic could affect in the knockout mice the range of effects associated with chronic exposure to this metalloid.
Description:
Michael F. Hughes, Brenda C. Edwards, Karen M. Herbin-Davis, David J. Thomas, Pharmacokinetics Branch, ISTD, NHEERL, ORO, US EPA, Research Triangle Park, NC Enzymatically catalyzed methylation of arsenic (As) determines its systemic distribution and retention and its actions as a toxicant and carcinogen. In the mouse, arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions that convert inorganic arsenic (iAs) to mono-and dimethylated metabolites. As3mt knockout (KO) mice exhibit a marked, albeit not complete, reduction in formation of methylated metabolites of iAs. We compared the distribution and retention of radioAs in adult female As3mt KO mice and wild type C567BL/6 mice. Each mouse received a daily oral dose of 0.5 mg of As as f 3As]-labeled arsenate per kg body weight and was radioassayed immediately before and after dosing to determine As body burden. Body burdens were at steady state after 10 daily doses. Dosing then ceased and As body burdens were measured in a washout period, during which body burdens declined to -50% (As3mt KO) or -65% (C57BL/6) of steady state levels. Tissues were collected at steady state and after washout. At steady state, As body burdens were -20-fold and tissue concentrations were -5 to 20-fold higher in As3mt KG mice than in C57BLl6 mice. At steady state, fractions of As body burden in skin, liver, urinary bladder, kidney, and brain of As3mt KG mice exceeded those in C57BLl6 mice. At the end of the washout period, phenotypic differences persisted in fractions of the body burden in these tissues. Taken together, these results show that diminished capacity for As methylation in As3mt KG mice affects tissue distribution of orally administered arsenate and the rate of tissue clearance of retained As. These changes would affect peak tissue contents of As and integrated exposure of a tissue to As. Altered tissue tropism or retention of As in As3mt KG mice could affect the range of toxic or carcinogenic effects associated with chronic exposure to this metalloid. (This abstract does not reflect U.S. EPA policy.)